Erectile dysfunction is a common disorder among male individuals worldwide. The introduction of sildenafil (the active ingredient in Viagra®) on the market in order to help patients with erectile problems has improved the possibilities to treat such disorders. Sildenafil and compounds closely related thereto are disclosed in EP 463 756, EP 702 555 and WO 98/49166 (all to Pfizer Ltd.). Other compounds useful as active ingredients in medicaments for the treatment of erectile dysfunction are disclosed in EP application no. 99850097.0.
Sexual stimulation leads to nitric oxide (NO) release from the nerve endings and endothelial cells in the spongy erectile tissue, known as corpus carvenosum, of the penis. NO switches on the enzyme guanylate cyclase, which converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). cGMP is a key second messenger vasodilator, which relaxes the vascular smooth muscle of the blood vessels of the corpus carvenosum, leading to a stronger blood flow and an erection. Thus, the presence of cGMP is the main promoter of erection since it prolongs the strong and rich blood flow in the corpus carvenosum, thus prolonging the erection. Cyclic nucleotides are degraded by a group of enzymes known collectively as phosphodiesterases (PDEs). They are a group of ten structurally closely related isoenzymes. Some of these isoenzymes are more specific to certain cyclic nucleotides than to others and they vary in their specificity and affinity. PDE type 5 (PDE5) is very specific for cGMP and has a main function in the corpus carvenosum and is thus a main factor in the erection process. Other isoenzymes exert their physiological actions by acting more specifically on other nucleotides such as cAMP.
Several PDE isoenzymes have been described being expressed and co-expressed in different tissues with many physiological effects. Many PDE inhibitors are not very specific, thus inhibiting a range of more than one PDE at the same time, which could cause a wide contraindication and toxic effects. PDE6 being widely expressed in the rods of the retina is a cyclic AMP (cAMP) specific PDE. cAMP is inhibited by other PDE inhibitors as well, including non-specific PDE5 inhibitors, especially at high concentration.
PDE5 is a cyclic GMP specific PDE with very low or negligible effect on cAMP, with k1>>>k2,
while other PDEs (including PDE6, PDE4, and PDE3) have higher affinity for cAMP. Some PDEs such as PDE10 hydrolyze both cAMP and cGMP effectively. In order to stop or seriously reduce cGMP breakdown by PDE5, selective inhibitors of PDE5 are proving to be an effective treatment for erectile dysfunction. These inhibitors selectively inhibit PDE5 by competitively binding with PDE5 active sites. This prevents the hydrolysis of cGMP to the inactive form 5′-GMP, allowing cGMP to accumulate and prolong the vasodilatation effect.Thus, there is a need for specific PDE5 inhibitors within the art, leading to the accumulation of cGMP. The inhibitors should at the same time have a very low or negligible effect on cAMP. High accumulation of cGMP and low effect on the levels of cAMP is a good indicator of the PDE5 inhibitor specificity.